U.S. Pat. No. 4,904,792 teaches that Nizatidine, N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-N'-methyl -2-nitro-1,1-ethenediamine, and related compounds of the general formula ##STR1## wherein
R.sup.1 is hydrogen, methyl, ethyl, benzyl or benzoyl; R.sup.2 is methyl or ethyl; or R.sup.1 and R.sup.2, taken together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidene or morpholine ring;
R.sup.3 is hydrogen or methyl;
Z is --O-- or --S--;
n is 2 or 3;
Q is ##STR2## wherein
A is N--CN, N--NO.sub.2, CH--NO.sub.2, S, N--SO.sub.2 --aryl, N--SO.sub.2 --methyl or N--CO--NH.sub.2 (where aryl is tolyl or phenyl); and
B is NHR, where R is methyl, ethyl, (2-hydroxy)ethyl or cyclopropyl, or YR.sup.4 where Y is --O-- or --S-- and R4 is C.sub.1 -C.sub.3 alkyl, --CH.sub.2 --(C.sub.2 -C.sub.4 alkenyl) or benzyl, are particularly effective H.sub.2 -receptor antagonists, or are useful as intermediates in the preparation of such pharmaceutically active compounds. As such, the patent compounds are useful as anti-ulcer agents capable of inhibiting gastric acid secretion in mammals. Nizatidine, in particular, is an effective anti-ulcer drug currently sold under the trademark AXID.
U.S. Pat. No. 4,904,792 discloses Nizatidine, and the other related compounds set forth in the patent, are synthesized using a multi-step process. The first step of this process comprises reacting an acid addition salt of an aminomethylthioacetamide with a beta-bromo-alpha-ketoester, such as ethyl bromopyruvate, so as to provide an alkyl-2-(aminomethyl)-4-thiazolecarboxylate. Reduction of such compound with a suitable hydride reducing agent yields a 2-(aminomethyl)-4-thiazolemethanol compound, which is then converted to a [2-(aminomethyl)-4-thiazolylmethylthio]alkylamine by reaction with cysteamine or 3-mercaptopropylamine in the presence of an acid. Such alkylamine is then readily converted to the pharmaceutically active compounds of the patent via several different reaction pathways.
The process disclosed in U.S. Pat. No. 4,904,792 has several disadvantages which limit its utility on a production scale setting. Firstly, several of the reactants required by the patent's process are rather expensive. Secondly, the process yield, on a production scale, is less than desirable. Finally, the purity of the final product (which is directly related to the purity of the alkylamine intermediate), when prepared on a production scale utilizing the procedure described above, is inconsistent and sometimes insufficient. When product of insufficient purity is obtained, such product must be recrystallized in order to increase purity to an acceptable level. Such recrystallization results in product loss thereby lowering process yield even further. All of these factors, when combined, render the process disclosed in U.S. Pat. No. 4,904,792 suitable for preparing laboratory scale quantities of product, but less than desirable for preparing production scale quantities of same.
Accordingly, an object of the present invention is to provide a process for preparing Nizatidine, and related compounds, which is eminently suitable for use in a production scale setting. The process of the present invention utilizes relatively inexpensive substrates to prepare the key alkylamine intermediate of U.S. Pat. No. 4,904,792. Furthermore, such key intermediate can be prepared in both high yield and purity. As such, the process of the present invention is believed to provide a more economical synthesis for particularly useful anti-ulcer agents than previously known routes for preparing such compounds.